Ask The Expert
January 8, 2014
When should a child with repeated skin infection of moderate to severe atopic dermatitis (4 to 6 courses of antibiotics annually), but with no infections elsewhere, be investigated for immunodeficiency?
By Dr. Juan Aldave Becerra:
Severe atopic dermatitis has several genetic and environmental pathogenic factors that affect the normal function of the immune system within the skin. I summarize them in the following list:
- Skin barrier defects: scratching; reduced synthesis of epidermal proteins such as filaggrin, loricrin, involucrin, corneodesmosin, S100 proteins, antiproteases and tight junction proteins (e.g. claudin-1).
- Innate immune dysregulation: increased number of inflammatory dendritic cells, altered TLR signalling, reduced production of antimicrobial peptides (e.g. cathelicidin, defensins), keratinocyte activation by environmental factors (e.g. allergen proteases, pollutants, microbes), increased keratinocyte production of cytokines that promote TH2 environment (e.g. TSLP, IL-25, IL-33), increased production of neuropeptides.
- Adaptive immune dysregulation: increased TH2 and TH22 inflammation, altered TH1 responses (predisposition to viral and bacterial infections), altered TH17 responses (predisposition to bacterial and fungal infections), and reduced Treg responses.
- Exaggerated immune responses to food allergens (e.g. milk, egg), aeroallergens (e.g. house dust mites), microbial molecules (e.g. from S aureus or Malassezia sp) or self antigens (e.g. human thioredoxin).
- Abnormal skin colonization by microbes: S aureus colonizes the skin in 90% of AD patients (staphylococcal enterotoxins induce polyclonal T-cell and B-cell activation).
In summary, severe atopic dermatitis per se generates a state of immunodeficiency in the skin, increasing the risk for cutaneous infections in affected patients, especially by S aureus and certain herpes virus (herpes simplex virus, varicella zoster virus). Additionally, there are gene defects and variants associated with severe atopic dermatitis, such as desmoglein 1, MATT1, filaggrin, TLR2, TLR4 and SPINK5.
On the other hand, we should note that some primary immunodeficiencies (PI) such as the hyper-IgE syndrome (HIES), Wiskott-Aldrich syndrome (WAS), and Netherton syndrome may initially present as severe atopic dermatitis, resulting in delayed diagnosis and treatment. There are no established clinical criteria that can absolutely exclude PI in patients with AD. However, in every patient with severe AD we should investigate family history of PI, positive history of recurrent infections apart from the skin, and other clinical details (e.g. coarse facial features, pneumatoceles, skeletal abnormalities, delayed shedding of primary teeth, low TH17 numbers and NIH score ≥40 in STAT3-defective HIES; thrombocytopenia with microplatelets in WAS; ‘bamboo hair’ in Netherton syndrome). Even more, we must consider that the clinical manifestations of PI are highly variable depending on the type of gene mutation, the degree of protein affection, gene-gene interactions, and the effect of environmental factors.
Please look below at a list of interesting articles that will help you.
- Eyerich k, Novak N. Immunology of atopic eczema: overcoming the TH1/TH2 paradigm. Allergy 2013; 68: 974–982.
- Sprecher E, Leung DYM. Atopic dermatitis: scratching through the complexity of barrier dysfunction. J Allergy Clin Immunol 2013; 132: 1130-1131.
- Kiyohara C , Tanaka K, Miyake Y. Genetic susceptibility to atopic dermatitis. Allergol Int. 2008; 57: 39-56.
- Samuelov L, Sarig O, Harmon RM, Rapaport D, Ishida-Yamamoto A, Isakov O, et al. Desmoglein 1 deficiency results in severe dermatitis, multiple allergies and metabolic wasting. Nat Genet 2013 [Epub ahead of print].
- Saunders SP, Goh CS, Brown SJ, Palmer CN, Porter RM, Cole C, et al. Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in humans. J Allergy Clin Immunol 2013; 132: 1121-1129.
- Zhao LP , Di Z, Zhang L, Wang L, Ma L, Lv Y, Hong Y, Wei H, Chen HD, Gao XH. Association of SPINK5 gene polymorphisms with atopic dermatitis in Northeast China. J Eur Acad Dermatol Venereol. 2012; 26: 572-577.
- Levchenko LIu , Izmai(lova OV, Shlykova OA, Kai(dashev IP. Polymorphism 896A/G of TLR4 gene rather than 1196C/T and 2258G/A of TLR2 gene determines severe and complicated course of atopic dermatitis in children. Tsitol Genet. 2013; 47: 46-53.
- Oh DY , Schumann RR, Hamann L, Neumann K, Worm M, Heine G. Association of the toll-like receptor 2 A-16934T promoter polymorphism with severe atopic dermatitis. Allergy 2009; 64: 1608-1615.
- De Benedetto A , Slifka MK, Rafaels NM, Kuo IH, Georas SN, Boguniewicz M, Hata T, Schneider LC, Hanifin JM, Gallo RL, Johnson DC,Barnes KC, Leung DY, Beck LA. Reductions in claudin-1 may enhance susceptibility to herpes simplex virus 1 infections in atopic dermatitis. J Allergy Clin Immunol. 2011; 128: 242-246.
- Prado-Montes de Oca E , García-Vargas A, Lozano-Inocencio R, Gallegos-Arreola MP, Sandoval-Ramírez L, Dávalos-Rodríguez NO, Figuera LE. Association of beta-defensin 1 single nucleotide polymorphisms with atopic dermatitis. Int Arch Allergy Immunol. 2007; 142: 211-218.
- Aghamohammadi A, Moghaddam ZG, Abolhassani H , Hallaji Z, Mortazavi H, Pourhamdi S, Mohammadinejad P, Rezaei N. Investigation of underlying primary immunodeficiencies in patients with severe atopic dermatitis. Allergol Immunopathol (Madr). 2013 [Epub ahead of print].
- Ohameje NU, Loveless JW, Saini SS . Atopic dermatitis or hyper-IgE syndrome? Allergy Asthma Proc. 2006; 27: 289-291.
- Schimke LF , Sawalle-Belohradsky J, Roesler J, Wollenberg A, Rack A, Borte M, Rieber N, Cremer R, Maass E, Dopfer R, Reichenbach J, Wahn V, Hoenig M, Jansson AF, Roesen-Wolff A, Schaub B, Seger R, Hill HR, Ochs HD, Torgerson TR, Belohradsky BH, Renner ED. Diagnostic approach to the hyper-IgE syndromes: immunologic and clinical key findings to differentiate hyper-IgE syndromes from atopic dermatitis. J Allergy Clin Immunol. 2010; 126: 611-617.
- Imai K , Nonoyama S, Ochs HD. WASP (Wiskott-Aldrich syndrome protein) gene mutations and phenotype. Curr Opin Allergy Clin Immunol. 2003; 3: 427-436.
- Saurat JH. Eczema in primary immune-deficiencies. Clues to the pathogenesis of atopic dermatitis with special reference to the Wiskott-Aldrich syndrome. Acta Derm Venereol Suppl (Stockh). 1985; 114: 125-128.
- D'Alessio M , Fortugno P, Zambruno G, Hovnanian A. Netherton syndrome and its multifaceted defective protein LEKTI. G Ital Dermatol Venereol. 2013 Feb; 148: 37-51.
- Igawa S, Kishibe M, Honma M, Murakami M, Mizuno Y, Suga Y, Seishima M, Ohguchi Y, Akiyama M, Hirose K, Ishida-Yamamoto A, Iizuka H. Aberrant distribution patterns of corneodesmosomal components of tape-stripped corneocytes in atopic dermatitis and related skin conditions (ichthyosis vulgaris, Netherton syndrome and peeling skin syndrome type B). J Dermatol Sci. 2013; 72: 54-60.
Juan Aldave Becerra, MD
Hospital Nacional Edgardo Rebagliati Martins
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